Located in the rich alluvial plain of the Ghab valley on the eastern side of the an-Nusayriyah Mountains (also known as Jebel Ansariye), the area has been continuously inhabited for over 10,000 years.

Although Jisr ash-Shughūr is mostly of modern construction, a number of old Ottoman-era buildings still survive, including a caravanserai built in the centre of the old town between 1660–75 and later restored in 1826–27.

For much of the 18th century, however, the town itself was controlled by the Kurdish agha (title) Muhammad ibn Rustum and his sons, first as kaymakam (deputy governor), then as mütevelli (manager) of the religious foundation of Köprülü Mehmed Pasha in Jisr ash-Shughūr.

In December 1920, the local rebel leader Ibrahim Hananu together with Kurdish bands from the Sahyun and with support of Kemalist insurgency forces from Turkey managed to seize the town from the French.

[12] The city has been described as conservative and predominantly Sunni Muslim, with a history of unrest against the government of the ruling secular Arab nationalist Baʻth.

Later that day, units of the Syrian Army Special Forces were helicoptered in from Aleppo to regain control, which they did after pounding the town with rockets and mortars, destroying homes and shops and killing and wounding dozens of people.

[17] The city was reported to have been largely abandoned by its inhabitants, many of whom fled to neighbouring Turkey, as Syrian Army units massed outside to retake it.

[20] However, on 25 April 2015, the city was captured by an alliance of Salafist insurgents, including al-Qaeda's al-Nusra Front, Ahrar al-Sham,[21][22] and the Turkistan Islamic Party (TIP).